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Despite advances in pharmacogenomics that have led to innovative therapeutic strategies, substantial interindividual variability in drug efficacy and toxicity persists. Both endogenous and exogenous factors contribute to this unexplained variation, resulting in suboptimal treatment effectiveness, unnecessary healthcare costs, preventable mortality, and significant human suffering. The emerging field of exposomics is aimed at addressing the complex exposures that impact human health and offers an opportunity to interrogate how these exposures influence drug actions and outcomes. Here, we introduce pharmacoexposomics as a complementary framework that systematically quantifies the body's metabolic response to drug and environmental exposures using high-resolution mass spectrometry. We then present IndiPHARM (Individualized Pharmacology), a multi-institution, Advanced Research Projects Agency for Health–supported platform designed to integrate population-scale pharmacoexposomics with pharmacogenomics and clinical data to elucidate interindividual variability in drug response, identify adverse reactions, and inform tailored, effective treatment strategies that advance precision medicine.

ABSTRACT Aims Metabolic dysfunction‐associated steatotic liver disease (MASLD) is increasingly linked to cognitive decline, yet the hepatic factors associated with imaging‐derived neurovascular coupling (NVC) remain unclear. This study aimed to investigate whether liver stiffness or liver fat content was more closely associated with resting‐state CBF‐ReHo surrogate measures. Materials and Methods A total of 130 participants including 98 MASLD patients and 32 age‐ and education‐matched healthy controls (HCs) underwent clinical assessment, neuropsychological testing, and multi‐modal MRI. Liver stiffness and fat content were quantified using MR elastography (MRE) and MRI‐proton density fat fraction (PDFF). Imaging‐derived NVC was assessed using global cerebral blood flow (CBF)‐regional homogeneity (ReHo) coupling and voxel‐wise CBF/ReHo ratios, interpreted as resting‐state surrogates rather than direct stimulus‐evoked NVC. Multivariable regression and exploratory mediation analyses were employed. Results Compared to HCs and patients with lower liver stiffness (MASLD_low), those with higher liver stiffness (MASLD_high) showed reduced global CBF‐ReHo coupling and altered CBF/ReHo ratios, primarily localized to the bilateral superior temporal pole/superior temporal gyrus (TPOsup). In multivariable regression, liver stiffness remained independently associated with TPOsup CBF/ReHo ratios ( p < 0.001). Exploratory mediation analysis showed a statistically significant indirect association between hepatocellular injury markers and TPOsup CBF/ReHo ratios involving MRE‐derived liver stiffness (95% CI: 0.0795–0.2790). Conclusions Within this cohort and the observed PDFF range, MRE‐derived liver stiffness was more closely associated with imaging‐derived NVC surrogate measures than liver fat content in MASLD. These findings are hypothesis‐generating and require validation in longitudinal studies.

Diffuse large B-cell lymphoma (DLBCL), the most common type of lymphoma, arises from various pathogenic mechanisms including gene translocations and fusions. Detection of gene rearrangements using fluorescence in situ hybridization (FISH) is a standard practice for DLBCL diagnosis and guides treatment decisions. High-throughput chromosome conformation capture (Hi-C) DNA sequencing is a next-generation sequencing-based technology to identify genome-wide rearrangements using a single assay. In this study, Hi-C sequencing was performed using FFPE tissues from 159 patients with DLBCL, and identified 746 cancer genes at or proximal to the rearrangement breakpoints with a total of 1903 occurrences. Focusing on clinically important rearrangements, Hi-C detected 102 rearrangements of MYC, BCL2, and/or BCL6 in 92 patients and revealed the fusion partners, including 25 rearrangements missed by FISH. Causes of FISH negative results included FISH-cryptic breakpoints, complex or faint FISH signals, low percentage of FISH positivity, and issues related to tissue fixation. Moreover, in 20 patients (12.6%), Hi-C sequencing detected 22 rearrangements characteristic of other lymphoma types, including CCND1 rearrangements that could lead to reclassification as mantle cell lymphoma. Survival analysis for genome-wide rearrangements using machine learning models identified MYC, PD-L1, CCND1, BCL2, NTRK1/PRCC, RRAS, and FANCE rearrangements with significant prognostic effects in the DLBCL cohort. In conclusion, Hi-C sequencing detects gene rearrangements crucial for diagnosis in an unbiased and molecular manner and showed high sensitivity and specificity in our study. These advantages of Hi-C sequencing offer help to improve the workflow of clinical pathology laboratories, diagnostic precision, and treatment of large B-cell lymphoma.

Objective: To evaluate the institutional learning curve of robotic liver resection (RLR), its association with surgical complexity and outcomes in an international multicenter cohort. Summary of Background Data: RLR is increasingly adopted worldwide, but the dynamics of the learning process and its impact on surgical outcomes remain poorly defined. Methods: This international, multicenter, retrospective cohort study included consecutive patients who underwent RLR between 06/2013 and 12/2024 across 22 expert centers. Based on the first 150 cases at each center, three phases were used to define the learning curve: operative time for competency, major complications for proficiency, and textbook outcome for mastery. Risk-adjusted generalized additive models were used to assess the learning process. Benchmark performance was compared to international reference values. Results: Among 2,331 patients, the most common indications were hepatocellular carcinoma (36%), benign lesions (23%) and colorectal liver metastases (21%). Operative time decreased after achieving competency (case #62), from 240 to 220 minutes ( P <0.001). Major morbidity reached a plateau during the proficiency phase (cases #63–138; 9% vs. 11%, P =0.144), while progression to mastery (cases #139–150) was associated with a higher rate of textbook outcome (76% vs. 87%, P =0.021). In contrast, conversion (5.1% vs. 4.9% vs. 2%), bile leak (4.0% vs. 5.3% vs. 3.8%), and 90-day mortality (0.7% vs. 0.9% vs. 0.9%) remained low and stable across all learning phases. Importantly, benchmark criteria for operative time, hospital stay, and textbook outcome were met across all complexity groups, including during the early learning phase. Conclusions: Robotic liver surgery shows progressive outcome improvement with early achievement of benchmark-level results and stable performance across increasing complexity. These findings indicate that, in experienced centers, RLR can be safely implemented and integrated into clinical practice, supporting its key role in modern hepatobiliary surgery.

Abstract Objective Invasive presurgical evaluation plays a key role in pediatric epilepsy surgery, particularly in magnetic resonance imaging (MRI)‐negative cases, by guiding resective, disconnective, or ablative procedures. This International League Against Epilepsy (ILAE) Pediatric Epilepsy Surgery Taskforce study provides an updated global overview of current invasive evaluation practices. Methods Group‐level data were collected from 61 epilepsy surgery programs (49 pediatric‐only) in 29 countries across six continents. Included were children and adolescents who underwent presurgical evaluation and epilepsy surgery in 2023. The study was designed to enable comparison with the similar ILAE survey conducted in 2004. Results A total of 2427 patients were included. Invasive evaluations were performed in 21.1% of cases, most frequently in North America (33.7%, higher than Europe: 18.0%, p = .003). Among invasive cases, 32.3% had no detectable MRI abnormalities. The main indication for invasive evaluation was seizure onset localization (88.1%), followed by motor or sensory mapping (17.2%) and language mapping (14.2%). Stereoelectroencephalography (SEEG) was the predominant technique (19.8% overall, 93.6% of invasive cases), more common in North America (30.0%, p = .021) and less common in South America (7.4%, p < .001). Subdural electrodes were used in only 3.2% of invasive cases, and combined depth and subdural approaches in 3.2%. SEEG‐guided radiofrequency thermocoagulation (RF‐TC) was performed in 40.9% of SEEG cases, most commonly in Asia (63.8%). In 16.2% of invasive evaluations, patients did not proceed to resection, disconnection, or ablation, with the highest rate in Europe (28.5%). Significance This global survey provides the first broad overview of invasive evaluation practices in pediatric epilepsy surgery across participating centers worldwide. It highlights the widespread adoption of SEEG, declining use of subdural electrodes, and increasing application of SEEG‐guided RF‐TC. The high proportion of MRI‐negative cases and the considerable proportion of patients not proceeding to resection, disconnection, or ablation underscore the complexity of contemporary surgical candidates and the need for further refinement of selection strategies.